Thanks

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Heavy mite exposure in the environment can induce allergic systemic reactions.

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Anaphylaxis

Anaphylaxis is an acute emergency that is potentially fatal and commonly related to an allergic and immunologic trigger requiring immediate effective life-saving treatment [151]. Heavy mite exposure in the environment can induce allergic systemic reactions. More recently, the induction of anaphylaxis through ingestion of mite-contaminated foods has been described [152].

Pancake anaphylaxis, also called oral mite anaphylaxis (OMA), is a relatively new syndrome characterized by severe allergic symptoms occurring immediately after eating foods, especially containing flours, contaminated with mites. These cooked foods contain thermoresistant mite allergens and contaminated wheat flour used to make pancakes is its most common presentation [152]. A variant clinical picture is provoked by physical exercise and is called dust mite ingestion-associated exercise-induced anaphylaxis [153]. OMA is more prevalent in tropical and subtropical areas of the globe where mites grow easily in their warm and humid environments [154]. There are reports in the literature of two fatalities associated with the ingestion of foods contaminated with mites [155, 156]. Mites responsible for OMA include domestic and storage species and can be present in any type of flours. There is an intriguing association of OMA and hypersensitivity to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS) for which there is no good explanation yet and it is more prevalent in patients with house dust mite allergic rhinitis and/or asthma [157]. The higher the contaminated mite ingestion the greater the risk for anaphylaxis. OMA confirmation requires the microscopic documentation and identification of mites in the suspected flour. Alternatively the immunoassay for demonstration of the presence of mite allergens in the suspected flour can be used. It is imperative to try to prevent the worldwide OMA delineating predisposing genetic factors and determining if mite immunotherapy might be efficacious modifying the clinical course of this important variety of food anaphylaxis [152, 158].

Co-sensitization to cockroaches, some crustaceans (shrimp, crab, lobster), shellfish (clams, mussels), and mollusks (snails) is often described and likely due to the presence of allergens in the tropomyosins family, present in some crustaceans (major allergen of shrimp: Pen 1), insects (some flies, mosquitoes, cockroaches), gastropods and mites (Der f 10) [122].

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Prevention of Dust Mite and Dust Mite Allergen Exposure

http://alexsfakianakis.blogspot.com/2017/05/mite-hypersensitivity.html

Justification for Dust Mite Exposure Control

The decision to initiate environmental controls to reduce dust mite exposure can be complex. Total prevention of exposure to mite allergenic material to prevent IgE sensitization to mite allergens in genetically susceptible individuals requires strict, continuous avoidance of mite exposure, which is practically all but impossible [199]. Furthermore, to curtail development of all cross-reacting specific IgE, avoidance of all arthropods would probably be required [200]. The majority of the world's population lives on seacoasts [201] or along rivers [202] and these areas typically have adequate humidity to support growth of dust mites and storage mites during all parts of the year.

Much research has been conducted to determine if it is possible to reduce development of mite-specific IgE-mediated sensitization (primary prevention). Several studies comparing dust mite sensitization rates in children from areas endemically low and areas endemically high in dust mite allergen indicated that the prevalence and degree of sensitization to dust mite was strongly associated with the amount of exposure to mite allergens [203, 204]. A prospective study of mite allergen avoidance in Manchester, UK, [205, 206] using a combination of interventions, decreased Der p 1 from mattresses by 97% to the nanogram range during pregnancy and 12 months after birth in the active group [205]. However, with all possible dust mite exposures at homes of friends and family, on public transportation and in public places and at schools and day care centers, primary prevention of dust mite sensitization by mite allergen avoidance may not be possible [207, 208, 209].

Secondary prevention, or the attempt to reduce the risk of asthma in dust mite sensitized children has also received much attention. The link between asthma and dust mite exposure is one of the most extensively studied relationships between environmental exposure and disease development [210, 211, 212, 213]. In all climates conducive to the growth of dust mites, mite exposure may be one of the factors contributing to the development of asthma [112, 214]. Secondary prevention has also been the goal for many children with allergic rhinitis who are at risk of the subsequent development of asthma. However, to date there is no evidence-based information as to whether mite avoidance may be effective as a secondary preventive measure to prevent/delay asthma development among mite-sensitized individuals, or those with allergic rhinitis.

The relation of dust mite allergen exposure and the worsening of allergic respiratory symptoms is well documented [215]. In one study of 311 subjects both sensitized and exposed to high levels of indoor allergen including dust mite allergen there was significantly lower FEV1% predicted values (mean, 83.7% vs 89.3%; mean difference, 5.6%; 95% CI, 0.6%-10.6%; P = .03), higher eNO values (geometric mean [GM], 12.8 vs 8.7 ppb; GM ratio, 0.7; 95% CI, 0.5-0.8; P = .001), and more severe airways reactivity (PD20 GM, 0.25 vs 0.73 mg; GM ratio, 2.9; 95% CI, 1.6-5.0; P < .001) as compared with subjects not sensitized and exposed [216]. Adults in a 4-year study who were both sensitized and exposed to high levels of dust mite allergens had increased bronchial hyper-responsiveness [217]. Many additional links between dust mite exposure and allergic disease are documented in the recent environmental practice parameter on dust mites [198]. A reduction in the symptoms experienced by those with atopic dermatitis has also been linked to house dust-mite allergen avoidance [218].

Facilitative factors and Allergen Reservoirs

Controlling factors that facilitate the growth and reproduction of dust mites has been an often sought goal in exposure control. The dependence of dust mites on the water content of the air has been extensively documented [219, 220]. Arid climates have an intrinsically low abundance of dust mites, and the most effective method of controlling dust mite exposure is to live in a very dry climate such as the high desert of New Mexico in the US or the Altiplano or Bolivian Plateau, in west-central South America [202]. Since this is not a practical solution, mimicking these conditions in the home environment as much as possible provides an opportunity to control mite population growth.

Humidity control should be the mainstay of any mite control efforts. The most important factor facilitating dust mite growth, reproduction and allergen production is the availability of water in the surrounding environment [220]. Mites absorb moisture directly from their surroundings under conditions of high moisture and lose water when moisture is low. The mite moisture equilibrium therefore is not directly relative humidity dependent. It is instead dependent of the moisture situation of the local microenvironment and the moisture retention ability of the mite's immediate surroundings such as carpet dust reservoirs or bedding. A simple measurement of relative humidity may not assure an environment free of dust mite activity. Microenvironments that exist in bedding, in carpet next to concrete or in pet lounging areas may provide adequate moisture for mite survival in climates not expected to have a mite presence. A mite surrounded by a hygroscopic microenvironment as moist bedding can survive much dryer conditions than would be expected. Of note, exposure to a moisture rich environment for only a short period can provide enough moisture for growth and metabolism [221].

Although directly linked to water content of the air in the calculation of relative humidity, temperature is also a factor in dust mite survival. Conditions at the extreme ends of the temperature spectrum, either to cold or to hot can impact mite survival although elevated temperature conditions tend to be more lethal than freezing. Mites and their eggs survive poorly when exposed to hot water and clothes dryers but survive during short periods of freezing conditions. The exposure to direct sunlight is an often forgotten factor in the destruction of dust mites [222].

It is not enough to address mite factors facilitating mite population growth. Reservoirs of mite allergen must also be eliminated. House dust mites can be found in any area of the home, however they are most often associated with certain indoor environments including the bedroom carpet, mattresses and bedding, frequently occupied upholstered furniture and in pet lounging areas [223, 224]. Recent investigations have questioned the traditional concepts of the location of dust mite reservoirs indicating that significant exposure can occur in public transportation conveyances and associated with work environments as well as clothing [207].

Climate Factors

Although residents of cold and arid climates are less likely to be exposed to house dust mites, the large majority of the world population is exposed to house dust mites. Nearly half of the people in the world live within 200 km of the coast where humidity levels are typically higher. The rate of population growth in coastal areas is accelerating. In China alone over 400 million live in coastal cities. Dust mite exposures and the allergic problems related to those exposures are likely to increase [201].

Although many climates are naturally conducive to mite growth and allergen production, the artificial control of indoor climates is increasing. Even though it is energy intensive, the use of forced air heating and air conditioning is growing around the world and especially in more affluent economies. Dust mite allergen exposure control is therefore a viable option for large numbers of persons. In many areas seasonal heating requirements result in very dry indoor environments and subsequently dust mite exposure is a seasonal phenomenon. Low humidity conditions can also be obtained through use of air conditioning and dehumidification. Yet, in many areas of the world ambient humidity levels are high enough that producing low humidity levels sufficient to preclude dust mite growth is not practically achievable. The recent Cochrane study on dehumidification alone indicates that evidence of clinical benefits of dehumidification using mechanical ventilation with dehumidifiers is scanty [225]. Indeed, the meta-analysis of multiple dust mite control studies would lead the reader to believe that there is nothing that can be physically done to control dust mites and improve health. Yet, this conclusion is disputed by many experts in the field of allergy [226]. Furthermore, the nature of single source exposure control studies may preclude successful clinical improvement because allergen sensitization is typically to multiple agents.

A significant amount of work has been done on removal of mites and mite allergens through cleaning. It goes without saying that efforts to control mite infestations of the skin and remove mite infestations from clothing are essential in the maintenance of overall health [227]. Humans have been living with dust mites for generations and they might even be described as among our "old friends" [228]. But no physician would advocate for wearing mite infested clothing or sleeping in mite infested bedding. Mite sensitization is likely to occur in genetically susceptible individuals, therefore efforts to reduce instances of elevated mite exposure and thus reduce allergic symptoms are only prudent [229].

Since mite allergens are located in known areas of a typical house [229, 230] removing mite allergen reservoirs is a very effective way to reduce mite allergen exposure. Efforts to remove carpets, drapes, upholstered furniture and any other fabric covered objects from the living environment can effectively reduce mite allergen exposure. The extent to which these items are removed will ultimately be a matter of personal preference. Since mite allergens are known to be heavy and not aerodynamically suited for airborne disbursal [34] and high humidity microenvironments are known to exist in bedding it is logical to focus dust mite reduction efforts on bedding. Efforts to enclose mattresses, box springs and pillows in mite-impermeable covers are known to be very effective [231]. However, it is important to mention that the efficacy of allergen avoidance in patients with already established rhinitis or asthma is a matter of debate [232, 233, 234, 235].

Washing bedding in hot water and even with bleach and drying bedding in very hot conditions or even in direct sunlight are known to reduce both the presence of mite allergen and the mites themselves [236, 237]. Washing bedding and clothing removes mite allergens and kills mites. Most of the killing is through drowning, although washing in hotter water kills more mites. The temperature used to wash bedding has become an issue. Elevated temperatures are more energy intensive and hotter water is a scalding hazard. Experts agree that washing is better than not washing and washing with water that is 48° Celsius provides optimum mite killing and home safety [199].

Heat treatment can be effective in killing mites and their eggs. Treatment of cloth at 95° Celsius killed all mites present [238]. However, treatment at 40 °C under dry and wet conditions allowed approximately 80% of all mite eggs to survive. Under dry heat at 50 °C, the thermal death point of dust mite eggs occurred at 5 h and at 60 °C death occurred almost instantaneously [239]. Presumably the eggs survive heat better than the mites themselves. Homes treated with heat-steam over a period of months showed a sustained reduction of Der p 1 and Der p 2 compared to sham treated homes [240] However, mite allergens have been demonstrated to be stable even at elevated temperatures [241].

Although the practice has fallen into senescence in the modern world of appliances, there was a time when frequently placing bedding in direct sunlight for several hours was practiced in many cultures. It has been demonstrated that ultraviolet irradiation is lethal to many organisms including dust mites [242, 243].

Many harsh chemicals are known to kill dust mites or denature mite allergens in industrial and household settings. Agents like tannic acid, Benzyl benzoate, Disodium octaborate tetrahydrate, tri-n-butyl tin maleate, pirimiphos methyl and even "essential oils" like methyl eugenol have been described in the literature to effectively kill mites [244, 245, 246, 247, 248]. However, they are all dangerous at some concentration and cannot be recommended for use by patients or homeowners [199].

It has been suggested that freezing can be effective in killing dust mites and the recommendation to place small cloth items like stuffed animals in the freezer compartment of house hold refrigerators has been frequently given out by allergists. However, there is little evidence that this is effective. There may be some mite death due to desiccation in the dry environment of a household freezer. But, dust mite eggs have been shown to resist freezing at temperatures above −70° Celsius [222]. And, freezing is not effective in removing dust mite allergen from reservoirs because dust mite allergen is stable at low temperatures for extended periods of time [239].

Air conditioning would have a twofold impact on dust mite populations. The cool temperatures will slow mite metabolism and reproduction and reduce moisture need for mite survival. Microenvironments or increased humidity can be reduced using a dehumidifier and/or air conditioning. The absence of air conditioning has been shown to be a factor contributing to increased mite allergen levels in US homes [249]. Air conditioners must be operated for a long time to remove sufficient moisture from the air to effectively decrease room humidity. Mechanical ventilation heat pump recovery units in the UK failed to achieve the desired mite reduction results [250].

Evidence on clinical benefits of dehumidification using mechanical ventilation with dehumidifiers remains scanty [225]. Although dehumidification and air conditioning doubtlessly reduce overall dust mite exposure [251], the difficulty in using dehumidification alone in damp environments to decrease dust mite antigen exposure has been described in a recent Cochrane review [225].

Summary of current recommendations

Most publications on allergy and dust mite control would agree that a comprehensive program of personal hygiene, bed hygiene, properly fitted allergen-impermeable covers, cleaning, dehumidification or air conditioning and appropriate food storage in very damp climates can reduce exposure to house dust mite allergens. It is a stretch further to conclude that the above steps can improve symptoms in those already allergic to dust mites. However, depending on the sensitivity and life style of the allergic person, prudent efforts over an extended period of time are likely to result in gradual improvement in health. The fact that current studies do not provide sufficient evidence for critical reviews to conclude there is unequivocal benefit is no reason to abandon logical and prudent efforts to reduce mite exposure.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Mite Allergy Research The authors view the following as currently unmet needs in mite allergy research: Since mites constitute the most important allergen source worldwide the information contained in this document needs to be disseminated to all ranks of the medical establishment for educational purposes and to stimulate research Increased knowledge on the cellular basis of the immune responses to mites A better understanding of the link between mite sensitization and allergic diseases Better insights into the genetic influences controlling IgE responses to mite allergens. Effects of epigenetic factors Improved mite allergen standardization Development of purified mite allergens with defined clinically relevant epitopes for molecular diagnosis and evaluation of the response to immunotherapy Development of objective methods to assess allergen exposure and environmental control outcomes Better strategies for immunotherapy and immunoprophylaxis of mite allergy: recombinant allergens, h

http://alexsfakianakis.blogspot.com/2017/05/mite-hypersensitivity.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Rick factors for medical and allergic events during air travel An increase of passenger’s age Flight stress and anxiety, including increased security procedures Disruption of routine Changes in the cabin environment (temperature, humidity, air pressure) Decreased seat space Flight delays Alcohol/drug intake Longer flights Altered circadian rhythm Jet lag Pre-existing medical conditions

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Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

In-flight treatment of allergic emergencies and asthma Treating medical emergencies during flight is a major challenge and air travel is an important concern for subjects with asthma and a history of a SAR. The resources to treat allergic emergencies are somewhat limited. In the United States, the Federal Aviation Administration requires the inclusion of epinephrine in medical kits carried on board [18]. These emergency medical kits typically contain the following medications [19]: Aqueous epinephrine (adrenaline) 1:10000 and 1:1000 dilution. Albuterol (salbutamol) for nebulization. Bronchodilator aerosol inhaler. Cortisol (hydrocortisone). Antihistamines tablets and injectable (commonly diphenhydramine). A recommendation from this World Allergy Organization (WAO) expert group for in-flight treatment of a SAR and AE is: a) For AE, inhaled bronchodilator and oxygen. Consider an oral, intramuscular or intravenous corticosteroid for moderate to severe symptoms and intramuscular epinephr

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Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Measures that reduce the risk of an in-flight reaction to peanut and tree nuts 1. Passengers requesting any kind of special accommodation (e.g., peanut/tree nut snacks not be distributed, announcement to not eat items with peanut/tree nut, request special peanut/tree nut-free meal, buffer zone, pre-board, request to sit in a certain seat/zone). 2. Peanut/tree nut-free meals. 3. Wiping of tray tables 4. Avoidance of airline pillows or blankets 5. Buffer zones around which peanut or nut products cannot be consumed 6. Request other passengers not to consume peanut/tree nut-containing products 7. Announcement that passengers do not eat peanut/tree nut containing goods 8. Not consuming airline-provided food

http://alexsfakianakis.blogspot.com/2017/05/in-flight-allergic-emergencies.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Recommendations to prevent and manage in-flight allergic events • Promote the prevention of allergic diseases via passenger education • Medical consultation for high-risk passengers before traveling • Train and re-train aircrews • Promote general preventive measures during the flight: hydration, food allergen avoidance (especially peanuts, tree nuts, other foods, as necessary) • Provide an appropriate place for furry pets away from subjects with pet allergy • Provide for sufficient quantities of appropriate medications: epinephrine (adrenaline), β2 agonists for inhalation and nebulization, oral and injectable corticosteroids and antihistamines • Oxygen

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Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Evaluation of intensity modulated radiation therapy dose painting for localized prostate cancer using 68Ga-HBED-CC PSMA-PET/CT: A planning study based on histopathology reference

To demonstrate the feasibility and to evaluate the tumour control probability (TCP) and normal tissue complication probability (NTCP) of IMRT dose painting using 68Ga-HBED-CC PSMA PET/CT for target delineation in prostate cancer (PCa).

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The multidisciplinary team approach for high-risk and major cancer surgery

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In This Issue

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In This Issue

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Non-invasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer

The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T™; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, though orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed 89Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a non-invasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with 89Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient-derived xenograft models.

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An miRNA expression signature for the human colonic stem cell niche distinguishes malignant from normal epithelia

Malignant transformation of tissue stem cells may be the root of most cancer. Accordingly, we identified miRNA expression patterns in the normal human colonic stem cell (SC) niche to understand how cancer stem cells (CSCs) may arise. In profiling miRNA expression in SC-enriched crypt subsections isolated from fresh, normal surgical specimens, we identified 16 miRNAs that were differentially expressed in the crypt bottom, creating a SC signature for normal colonic epithelia (NCE). A parallel analysis of colorectal cancer (CRC) tissues showed differential expression of 83 miRNAs relative to NCE. Within the 16 miRNA signature for the normal SC niche, we found that miRNA-206, miRNA-007-3 and miRNA-23b individually could distinguish CRC from NCE. Notably, miRNA-23b, which was increased in CRC, was predicted to target the SC-expressed G protein-coupled receptor LGR5. Cell biology investigations showed that miRNA-23b regulated CSC phenotypes globally at the level of proliferation, cell-cycle, self-renewal, EMT, invasion, and resistance to the CRC chemotherapeutic agent 5-FU. In mechanistic experiments we found that miRNA-23b decreased LGR5 expression and increased ALDH+ CSCs. CSC analyses confirmed that levels of LGR5 and miRNA-23b are inversely correlated in ALDH+ CSCs and that distinct sub-populations of LGR5+ and ALDH+ CSCs exist. Overall, our results define a critical function for miRNA-23b, which, by targeting LGR5, contributes to overpopulation of ALDH+ CSCs and CRC.

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Immune-related gene expression profiling after PD-1 blockade in non-small cell lung carcinoma, head and neck squamous cell carcinoma and melanoma.

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor speciments from 65 patients with melanoma, lung non-squamous, squamous cell lung or head and neck cancers who were treated with the approved PD1 targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). Additionally, we evaluated intra- and inter-biopsy variability of PD1, PDL1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 immunohistochemical expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T cell activation, natural killer (NK) cells and interferon activation associated significantly with non-progressive disease and PFS. These associations were independent of sample timing, drug used or cancer type. TIL correlated moderately (~0.50) with PD1 and CD8A mRNA levels and weakly (~0.35) with CD4 and PDL1. Immunochemical expression of PDL1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and inter-biopsy specimens was very high (total standard deviation <3%). Overall, our results support the hypothesis that identification of a pre-existing and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients.

http://ift.tt/2qPWQ7t

An miRNA expression signature for the human colonic stem cell niche distinguishes malignant from normal epithelia

Malignant transformation of tissue stem cells may be the root of most cancer. Accordingly, we identified miRNA expression patterns in the normal human colonic stem cell (SC) niche to understand how cancer stem cells (CSCs) may arise. In profiling miRNA expression in SC-enriched crypt subsections isolated from fresh, normal surgical specimens, we identified 16 miRNAs that were differentially expressed in the crypt bottom, creating a SC signature for normal colonic epithelia (NCE). A parallel analysis of colorectal cancer (CRC) tissues showed differential expression of 83 miRNAs relative to NCE. Within the 16 miRNA signature for the normal SC niche, we found that miRNA-206, miRNA-007-3 and miRNA-23b individually could distinguish CRC from NCE. Notably, miRNA-23b, which was increased in CRC, was predicted to target the SC-expressed G protein-coupled receptor LGR5. Cell biology investigations showed that miRNA-23b regulated CSC phenotypes globally at the level of proliferation, cell-cycle, self-renewal, EMT, invasion, and resistance to the CRC chemotherapeutic agent 5-FU. In mechanistic experiments we found that miRNA-23b decreased LGR5 expression and increased ALDH+ CSCs. CSC analyses confirmed that levels of LGR5 and miRNA-23b are inversely correlated in ALDH+ CSCs and that distinct sub-populations of LGR5+ and ALDH+ CSCs exist. Overall, our results define a critical function for miRNA-23b, which, by targeting LGR5, contributes to overpopulation of ALDH+ CSCs and CRC.

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Immune-related gene expression profiling after PD-1 blockade in non-small cell lung carcinoma, head and neck squamous cell carcinoma and melanoma.

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor speciments from 65 patients with melanoma, lung non-squamous, squamous cell lung or head and neck cancers who were treated with the approved PD1 targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). Additionally, we evaluated intra- and inter-biopsy variability of PD1, PDL1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 immunohistochemical expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T cell activation, natural killer (NK) cells and interferon activation associated significantly with non-progressive disease and PFS. These associations were independent of sample timing, drug used or cancer type. TIL correlated moderately (~0.50) with PD1 and CD8A mRNA levels and weakly (~0.35) with CD4 and PDL1. Immunochemical expression of PDL1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and inter-biopsy specimens was very high (total standard deviation <3%). Overall, our results support the hypothesis that identification of a pre-existing and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients.

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Monitoring tumor response to anti-vascular therapy using non-contrast intravoxel incoherent motion diffusion-weighted MRI

Anti-vascular therapy is a promising approach to the treatment of non-small-cell lung cancer (NSCLC), where an imaging modality capable of longitudinally monitoring treatment response could provide early prediction of the outcome. In this study, we sought to investigate the feasibility of using intravoxel incoherent motion (IVIM) diffusion MRI to quantitatively assess the efficacy of the treatments of a vascular disrupting agent CA4P or its combination with bevacizumab (BV) on experimental NSCLC tumors. CA4P caused a strong but reversible effect on tumor vasculature: all perfusion-related parameters-D*, f, fD*, and Ktrans-initially showed a decrease of 30%-60% at two hours and then fully recovered to baseline on day 2 for CA4P treatment or on days 4-8 for CA4P + BV treatment; the diffusion coefficient in tumors decreased initially at two hours and then increased from day 2 to day 8. We observed a good correlation between IVIM parameters and DCE-MRI (Ktrans). We also found that the relative change in f and fD* at two hours correlated well with changes in tumor volume on day 8. In conclusion, our results suggest that IVIM is a promising alternative to DCE-MRI for the assessment of the change in tumor perfusion as a result of anti-vascular agents and can be used to predict the efficacy of anti-vascular therapies without the need for contrast media injection.

http://ift.tt/2qQ6yH8

Non-invasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer

The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T™; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, though orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed 89Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a non-invasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with 89Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient-derived xenograft models.

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Monitoring tumor response to anti-vascular therapy using non-contrast intravoxel incoherent motion diffusion-weighted MRI

Anti-vascular therapy is a promising approach to the treatment of non-small-cell lung cancer (NSCLC), where an imaging modality capable of longitudinally monitoring treatment response could provide early prediction of the outcome. In this study, we sought to investigate the feasibility of using intravoxel incoherent motion (IVIM) diffusion MRI to quantitatively assess the efficacy of the treatments of a vascular disrupting agent CA4P or its combination with bevacizumab (BV) on experimental NSCLC tumors. CA4P caused a strong but reversible effect on tumor vasculature: all perfusion-related parameters-D*, f, fD*, and Ktrans-initially showed a decrease of 30%-60% at two hours and then fully recovered to baseline on day 2 for CA4P treatment or on days 4-8 for CA4P + BV treatment; the diffusion coefficient in tumors decreased initially at two hours and then increased from day 2 to day 8. We observed a good correlation between IVIM parameters and DCE-MRI (Ktrans). We also found that the relative change in f and fD* at two hours correlated well with changes in tumor volume on day 8. In conclusion, our results suggest that IVIM is a promising alternative to DCE-MRI for the assessment of the change in tumor perfusion as a result of anti-vascular agents and can be used to predict the efficacy of anti-vascular therapies without the need for contrast media injection.

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HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Purpose: Resistance to anti-HER2 therapies in HER2+ breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2+ breast cancer can reactivate the HER network under potent HER2-targeted therapies. <p>Experimental Design: Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER+/HER2+ BT474 cell lines (AZ/ATCC). Two derivatives resistant to the L-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared to parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition.</p> <p>Results: Genomic analyses revealed that the HER2L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2L755S induced acquired L resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2 irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2L755Sin vitro and in vivo.</p> <p>Conclusion: HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to L-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. 

http://ift.tt/2q1OZmv

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Purpose: Resistance to anti-HER2 therapies in HER2+ breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2+ breast cancer can reactivate the HER network under potent HER2-targeted therapies. <p>Experimental Design: Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER+/HER2+ BT474 cell lines (AZ/ATCC). Two derivatives resistant to the L-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared to parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition.</p> <p>Results: Genomic analyses revealed that the HER2L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2L755S induced acquired L resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2 irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2L755Sin vitro and in vivo.</p> <p>Conclusion: HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to L-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. 

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The longitudinal transcriptional response to neoadjuvant chemotherapy with and without bevacizumab in breast cancer.

Purpose: Chemotherapy induced alterations to gene expression are due to transcriptional reprogramming of tumor cells or subclonal adaptations to treatment. The effect on whole-transcriptome mRNA expression was investigated in a randomized phase II clinical trial to assess the effect of neoadjuvant chemotherapy with the addition of bevacizumab. <br />Experimental Design: Tumor biopsies and whole-transcriptome mRNA profiles were obtained at three fixed time points with 66 patients in each arm.  Altogether, 358 specimens from 132 patients were available, representing the transcriptional state before treatment start, at 12 weeks and after treatment (25 weeks). Pathological complete response (pCR) in breast and axillary nodes was the primary endpoint.<br />Results: Pathological complete response (pCR) was observed in 15 patients (23%) receiving bevacizumab and chemotherapy and 8 patients (12%) receiving only chemotherapy. In the estrogen receptor positive patients, 11 out of 54 (20%) treated with bevacizumab and chemotherapy achieved pCR, while only 3 out of 57 (5%) treated with chemotherapy reached pCR. In patients with estrogen receptor positive tumors treated with combination therapy, an elevated immune activity was associated with good response. Proliferation was reduced after treatment in both treatment arms and most pronounced in the combination therapy arm, where the reduction in proliferation accelerated during treatment. Transcriptional alterations during therapy were subtype specific, and the effect of adding bevacizumab was most evident for Luminal B tumors. <br />Conclusion:  Clinical response and gene expression response differed between patients receiving combination therapy and chemotherapy alone. The results may guide identification of patients likely to benefit from anti-angiogenic therapy.

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The longitudinal transcriptional response to neoadjuvant chemotherapy with and without bevacizumab in breast cancer.

Purpose: Chemotherapy induced alterations to gene expression are due to transcriptional reprogramming of tumor cells or subclonal adaptations to treatment. The effect on whole-transcriptome mRNA expression was investigated in a randomized phase II clinical trial to assess the effect of neoadjuvant chemotherapy with the addition of bevacizumab. <br />Experimental Design: Tumor biopsies and whole-transcriptome mRNA profiles were obtained at three fixed time points with 66 patients in each arm.  Altogether, 358 specimens from 132 patients were available, representing the transcriptional state before treatment start, at 12 weeks and after treatment (25 weeks). Pathological complete response (pCR) in breast and axillary nodes was the primary endpoint.<br />Results: Pathological complete response (pCR) was observed in 15 patients (23%) receiving bevacizumab and chemotherapy and 8 patients (12%) receiving only chemotherapy. In the estrogen receptor positive patients, 11 out of 54 (20%) treated with bevacizumab and chemotherapy achieved pCR, while only 3 out of 57 (5%) treated with chemotherapy reached pCR. In patients with estrogen receptor positive tumors treated with combination therapy, an elevated immune activity was associated with good response. Proliferation was reduced after treatment in both treatment arms and most pronounced in the combination therapy arm, where the reduction in proliferation accelerated during treatment. Transcriptional alterations during therapy were subtype specific, and the effect of adding bevacizumab was most evident for Luminal B tumors. <br />Conclusion:  Clinical response and gene expression response differed between patients receiving combination therapy and chemotherapy alone. The results may guide identification of patients likely to benefit from anti-angiogenic therapy.

http://ift.tt/2q4tSOi

Erratum to: Contribution of tumor endothelial cells to drug resistance: anti-angiogenic tyrosine kinase inhibitors act as p-glycoprotein antagonists

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Erratum to: Contribution of tumor endothelial cells to drug resistance: anti-angiogenic tyrosine kinase inhibitors act as p-glycoprotein antagonists

http://ift.tt/2qp7baO

Use of moist oral snuff (snus) and pancreatic cancer: Pooled analysis of nine prospective observational studies

Abstract

While smoking is a well-established risk factor for pancreatic cancer, the effect of smokeless tobacco is less well understood. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess the association between Swedish snus use and the risk of pancreatic cancer. A total of 424,152 male participants from nine cohort studies were followed up for risk of pancreatic cancer through linkage to health registers. We used shared frailty models with random effects at the study level, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for confounding factors. During 9,276,054 person-years of observation, 1,447 men developed pancreatic cancer. Compared to never snus use, current snus use was not associated with risk of pancreatic cancer (HR 0.96, 95% CI 0.83 – 1.11) after adjustment for smoking. Swedish snus use does not appear to be implicated in the development of pancreatic cancer in men. Tobacco smoke constituents other than nicotine or its metabolites may account for the relationship between smoking and pancreatic cancer. This article is protected by copyright. All rights reserved.

http://ift.tt/2qXyBke

Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study

Abstract

Kaposiform hemangioendothelioma (KHE) is an aggressive disease with high morbidity and mortality. The aim of this study was to retrospectively evaluate the efficacy and safety of sirolimus for the treatment of progressive KHE. A multicenter, retrospective cohort study was conducted in patients with progressive KHE treated with sirolimus. A total of 52 patients were analyzed. Thirty-seven (71%) patients exhibited Kasabach-Merritt phenomenon (KMP) and were significantly younger than the patients without KMP (95% confidence interval [CI], 14.39-41.61; P<0.001). Patients without KMP were all treated with sirolimus alone, whereas 21 KMP patients with severe symptoms received short-term combination therapy with prednisolone. Overall, 96% and 98% of patients showed improved relief of notable symptoms and/or improved complications at 6 and 12 months after treatment, respectively. After sirolimus treatment, significant decreases in mean severity scores occurred at 6 (95% CI, 2.23-2.54, P<0.001) and 12 (95% CI, 1.53-1.90, P<0.001) months. Compared with KMP patients, patients without KMP showed a response that was similar to but less pronounced during the 12 months of treatment (95% CI, 40.87-53.80; P<0.001). For subgroup analysis of KMP patients, there were no significant differences in tumor shrinkage between those treated with combination therapy and those receiving sirolimus alone (95% CI, 18.11-25.02; P>0.05). No patients permanently discontinued treatment due to toxicity-related events, and no drug-related deaths occurred. Sirolimus was effective and safe for the treatment of progressive KHE. Sirolimus may be considered as a first-line therapy or as part of a multidisciplinary approach for the treatment of KHE. This article is protected by copyright. All rights reserved.

http://ift.tt/2qXA5uC

Dietary intake of selected nutrients and persistence of HPV infection in men

Abstract

Human papillomavirus (HPV) infection is a common sexually transmitted disease. Although often transitory, persistent oncogenic HPV infection may progress to a precursor lesion and, if not treated, can further increase the risk of cancer. The purpose of this study was to investigate the relation between dietary intake and HPV persistent infection in men of a Brazilian cohort. The study population consisted of 1248 men from the Brazilian cohort of the HIM (HPV in Men) Study, ages 18 to 70 years, who completed a quantitative food frequency questionnaire. U Mann-Whitney test was used to assess differences in median nutrient intake of selected nutrients. The association of dietary intake and persistent HPV infection was assessed in multivariate logistic models. The prevalence of any HPV infection at baseline was 66.6%. Of 1248 participants analyzed, 1211 (97.0%) were HPV positive at one or more times during the 4 years of follow-up and 781 (62.6%) were persistently HPV positive. Men with non-persistent oncogenic HPV infections had higher median intake of retinol (p=0.008), vitamin A (p<0.001) and folate (DFE) (p=0.003), and lower median intake of energy (p=0.005) and lycopene (p=0.008) in comparison to men with persistent oncogenic infections. No significant association was found between selected nutrients and persistent oncogenic HPV infection. For non-oncogenic persistent infections, only vitamin B12 intake was significantly associated (p=0.003, test for trend). No association was observed between dietary intake and persistent oncogenic-type HPV infection; however, vitamin B12 intake was inversely associated with non-oncogenic HPV persistence. This article is protected by copyright. All rights reserved.

http://ift.tt/2pi4FTp

Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53

Abstract

Breast cancer among Palestinian women has lower incidence than in Europe or North America, yet is very frequently familial. We studied genetic causes of this familial clustering in a consecutive hospital-based series of 875 Palestinian patients with invasive breast cancer, including 453 women with diagnosis by age 40, or with breast or ovarian cancer in a mother, sister, grandmother, or aunt ("discovery series"); and 422 women diagnosed after age 40 and with negative family history ("older-onset sporadic patient series"). Genomic DNA from women in the discovery series was sequenced for all known breast cancer genes, revealing a pathogenic mutation in 13% (61/453) of patients. These mutations were screened in all patients and in 300 Palestinian female controls, revealing 1.0% (4/422) carriers among older, non-familial patients and two carriers among controls. The mutational spectrum was highly heterogeneous, including pathogenic mutations in eleven different genes: BRCA1, BRCA2, TP53, ATM, CHEK2, BARD1, BRIP1, PALB2, MRE11A, PTEN, and XRCC2. BRCA1 carriers were significantly more likely than other patients to have triple negative tumors (P = 0.03). The single most frequent mutation was TP53 p.R181C, which was significantly enriched in the discovery series compared to controls (P = 0.01) and was responsible for 15% of breast cancers among young onset or familial patients. TP53 p.R181C predisposed specifically to breast cancer with incomplete penetrance, and not to other Li-Fraumeni cancers. Palestinian women with young onset or familial breast cancer and their families would benefit from genetic analysis and counseling. This article is protected by copyright. All rights reserved.

http://ift.tt/2qXqJPR

Quantitative proteomics to study a small molecule targeting the loss of VHL

ABSTRACT

Inactivation of the tumor suppressor gene, von Hippel-Lindau (VHL) is known to play an important role in the development of sporadic clear cell Renal Cell Carcinomas (ccRCCs). Even if available targeted therapies for metastatic RCCs (mRCCs) have helped to improve progression-free survival rates, they have no durable clinical response. We have previously shown the feasibility of specifically targeting the loss of VHL with the identification of a small molecule, STF-62247. Understanding its functionality is crucial for developing durable personalized therapeutic agents differing from those available targeting Hypoxia Inducible Factor (HIF-) pathways. By using SILAC proteomics, we identified 755 deregulated proteins in response to STF-62247 that were further analyzed by Ingenuity Pathway Analysis (IPA). Bioinformatics analyses predicted alterations in 37 signaling pathways in VHL-null cells in response to treatment. Validation of some altered pathways shows that STF-62247's selectivity is linked to an important inhibition of mTORC1 activation in VHL-null cells leading to protein synthesis arrest, a mechanism differing from two allosteric inhibitors Rapamycin and Everolimus. Altogether, this study identified signaling cascades driving STF-62247 response and brings further knowledge for this molecule that shows selectivity for the loss of VHL. The use of a global SILAC approach was successful in identifying novel affected signaling pathways that could be exploited for the development of new personalized therapeutic strategies to target VHL-inactivated RCCs. This article is protected by copyright. All rights reserved.

http://ift.tt/2phJG3n

A phase I trial of concurrent sorafenib and stereotactic radiosurgery for patients with brain metastases

Abstract

We hypothesized that sorafenib (BAY 43-9006), an oral multi-kinase inhibitor, used in combination with SRS will improve overall intracranial control. This Phase I study assesses the safety, tolerability, and maximal tolerated dose of sorafenib administered with SRS to treat 1–4 brain metastases. This was an open label phase I dose escalation study with an expansion cohort. Eligible adults had 1–4 brain metastases from solid malignancies. Sorafenib was begun 5–7 days prior to SRS and continued for 14 days thereafter. Dose escalation of sorafenib was conducted via a "3 + 3" dose escalation design. Dose limiting toxicities (DLT) were determined 1 month after SRS and defined as ≥grade 3 neurologic toxicities. Twenty-three patients were enrolled. There were no DLTs at dose level 1 (400 mg per day) or dose level 2 (400 mg twice per day). An expansion cohort of 17 patients was treated at dose level 2. There were six grade 3 toxicities: hypertension (n = 2), rash (n = 1), lymphopenia (n = 1), hypokalemia (n = 1), fatigue (n = 1) and hand-foot syndrome (n = 1). All of these were attributable to sorafenib and not to the combination with SRS. The median time to CNS progression was 10 months, 1 year CNS progression-free survival was 46%, the median overall survival was 11.6 months and the 1 year overall survival was 46%. The use of sorafenib concurrent with SRS for the treatment of 1–4 brain metastases is safe and well tolerated at 400 mg twice a day. Our recommended phase II dose of concurrent sorafenib with SRS would be 400 mg twice daily.

http://ift.tt/2phQeie

SPECT imaging and radionuclide therapy of glioma using 131 I labeled Buthus martensii Karsch chlorotoxin

Abstract

Gliomas, the most prevalent type of brain tumor in adults, are associated with high rates of morbidity and mortality. Recent studies on ¹³¹I labeled scorpion toxins suggest they can be developed as tumor-specific agents for glioma diagnosis and treatment. This study investigated the potential of ¹³¹I labeled Buthus martensii Karsch chlorotoxin (¹³¹I-BmK CT) as a new approach for targeted imaging and therapy of glioma. The results showed that ¹³¹I can be successfully linked to BmK CT with satisfactory radiochemical purity and stability and that ¹³¹I-BmK CT markedly inhibited glioma cell growth in a dose and time dependent manner, with significant accumulation in glioma cells in vitro. Persistent intratumoral radioiodine retention and specific accumulation of ¹³¹I-BmK CT were observed in C6 glioma tumor, which was clearly visualized by SPECT imaging. Both intratumoral and intravenous injections of ¹³¹I-BmK CT could result in significant tumor inhibition efficacy and prolonging the lifetime of tumor-bearing mice. Based on these promising results, it is concluded that ¹³¹I-BmK CT has the potential to be explored as a novel tool for SPECT imaging and radionuclide therapy of glioma.

http://ift.tt/2q2nIyk

Dietary intake of selected nutrients and persistence of HPV infection in men

Abstract

Human papillomavirus (HPV) infection is a common sexually transmitted disease. Although often transitory, persistent oncogenic HPV infection may progress to a precursor lesion and, if not treated, can further increase the risk of cancer. The purpose of this study was to investigate the relation between dietary intake and HPV persistent infection in men of a Brazilian cohort. The study population consisted of 1248 men from the Brazilian cohort of the HIM (HPV in Men) Study, ages 18 to 70 years, who completed a quantitative food frequency questionnaire. U Mann-Whitney test was used to assess differences in median nutrient intake of selected nutrients. The association of dietary intake and persistent HPV infection was assessed in multivariate logistic models. The prevalence of any HPV infection at baseline was 66.6%. Of 1248 participants analyzed, 1211 (97.0%) were HPV positive at one or more times during the 4 years of follow-up and 781 (62.6%) were persistently HPV positive. Men with non-persistent oncogenic HPV infections had higher median intake of retinol (p=0.008), vitamin A (p<0.001) and folate (DFE) (p=0.003), and lower median intake of energy (p=0.005) and lycopene (p=0.008) in comparison to men with persistent oncogenic infections. No significant association was found between selected nutrients and persistent oncogenic HPV infection. For non-oncogenic persistent infections, only vitamin B12 intake was significantly associated (p=0.003, test for trend). No association was observed between dietary intake and persistent oncogenic-type HPV infection; however, vitamin B12 intake was inversely associated with non-oncogenic HPV persistence. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2pi4FTp
via IFTTT

Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study

Abstract

Kaposiform hemangioendothelioma (KHE) is an aggressive disease with high morbidity and mortality. The aim of this study was to retrospectively evaluate the efficacy and safety of sirolimus for the treatment of progressive KHE. A multicenter, retrospective cohort study was conducted in patients with progressive KHE treated with sirolimus. A total of 52 patients were analyzed. Thirty-seven (71%) patients exhibited Kasabach-Merritt phenomenon (KMP) and were significantly younger than the patients without KMP (95% confidence interval [CI], 14.39-41.61; P<0.001). Patients without KMP were all treated with sirolimus alone, whereas 21 KMP patients with severe symptoms received short-term combination therapy with prednisolone. Overall, 96% and 98% of patients showed improved relief of notable symptoms and/or improved complications at 6 and 12 months after treatment, respectively. After sirolimus treatment, significant decreases in mean severity scores occurred at 6 (95% CI, 2.23-2.54, P<0.001) and 12 (95% CI, 1.53-1.90, P<0.001) months. Compared with KMP patients, patients without KMP showed a response that was similar to but less pronounced during the 12 months of treatment (95% CI, 40.87-53.80; P<0.001). For subgroup analysis of KMP patients, there were no significant differences in tumor shrinkage between those treated with combination therapy and those receiving sirolimus alone (95% CI, 18.11-25.02; P>0.05). No patients permanently discontinued treatment due to toxicity-related events, and no drug-related deaths occurred. Sirolimus was effective and safe for the treatment of progressive KHE. Sirolimus may be considered as a first-line therapy or as part of a multidisciplinary approach for the treatment of KHE. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2qXA5uC
via IFTTT

Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53

Abstract

Breast cancer among Palestinian women has lower incidence than in Europe or North America, yet is very frequently familial. We studied genetic causes of this familial clustering in a consecutive hospital-based series of 875 Palestinian patients with invasive breast cancer, including 453 women with diagnosis by age 40, or with breast or ovarian cancer in a mother, sister, grandmother, or aunt ("discovery series"); and 422 women diagnosed after age 40 and with negative family history ("older-onset sporadic patient series"). Genomic DNA from women in the discovery series was sequenced for all known breast cancer genes, revealing a pathogenic mutation in 13% (61/453) of patients. These mutations were screened in all patients and in 300 Palestinian female controls, revealing 1.0% (4/422) carriers among older, non-familial patients and two carriers among controls. The mutational spectrum was highly heterogeneous, including pathogenic mutations in eleven different genes: BRCA1, BRCA2, TP53, ATM, CHEK2, BARD1, BRIP1, PALB2, MRE11A, PTEN, and XRCC2. BRCA1 carriers were significantly more likely than other patients to have triple negative tumors (P = 0.03). The single most frequent mutation was TP53 p.R181C, which was significantly enriched in the discovery series compared to controls (P = 0.01) and was responsible for 15% of breast cancers among young onset or familial patients. TP53 p.R181C predisposed specifically to breast cancer with incomplete penetrance, and not to other Li-Fraumeni cancers. Palestinian women with young onset or familial breast cancer and their families would benefit from genetic analysis and counseling. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2qXqJPR
via IFTTT

Quantitative proteomics to study a small molecule targeting the loss of VHL

ABSTRACT

Inactivation of the tumor suppressor gene, von Hippel-Lindau (VHL) is known to play an important role in the development of sporadic clear cell Renal Cell Carcinomas (ccRCCs). Even if available targeted therapies for metastatic RCCs (mRCCs) have helped to improve progression-free survival rates, they have no durable clinical response. We have previously shown the feasibility of specifically targeting the loss of VHL with the identification of a small molecule, STF-62247. Understanding its functionality is crucial for developing durable personalized therapeutic agents differing from those available targeting Hypoxia Inducible Factor (HIF-) pathways. By using SILAC proteomics, we identified 755 deregulated proteins in response to STF-62247 that were further analyzed by Ingenuity Pathway Analysis (IPA). Bioinformatics analyses predicted alterations in 37 signaling pathways in VHL-null cells in response to treatment. Validation of some altered pathways shows that STF-62247's selectivity is linked to an important inhibition of mTORC1 activation in VHL-null cells leading to protein synthesis arrest, a mechanism differing from two allosteric inhibitors Rapamycin and Everolimus. Altogether, this study identified signaling cascades driving STF-62247 response and brings further knowledge for this molecule that shows selectivity for the loss of VHL. The use of a global SILAC approach was successful in identifying novel affected signaling pathways that could be exploited for the development of new personalized therapeutic strategies to target VHL-inactivated RCCs. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2phJG3n
via IFTTT

Use of moist oral snuff (snus) and pancreatic cancer: Pooled analysis of nine prospective observational studies

Abstract

While smoking is a well-established risk factor for pancreatic cancer, the effect of smokeless tobacco is less well understood. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess the association between Swedish snus use and the risk of pancreatic cancer. A total of 424,152 male participants from nine cohort studies were followed up for risk of pancreatic cancer through linkage to health registers. We used shared frailty models with random effects at the study level, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for confounding factors. During 9,276,054 person-years of observation, 1,447 men developed pancreatic cancer. Compared to never snus use, current snus use was not associated with risk of pancreatic cancer (HR 0.96, 95% CI 0.83 – 1.11) after adjustment for smoking. Swedish snus use does not appear to be implicated in the development of pancreatic cancer in men. Tobacco smoke constituents other than nicotine or its metabolites may account for the relationship between smoking and pancreatic cancer. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2qXyBke
via IFTTT

A phase I trial of concurrent sorafenib and stereotactic radiosurgery for patients with brain metastases

Abstract

We hypothesized that sorafenib (BAY 43-9006), an oral multi-kinase inhibitor, used in combination with SRS will improve overall intracranial control. This Phase I study assesses the safety, tolerability, and maximal tolerated dose of sorafenib administered with SRS to treat 1–4 brain metastases. This was an open label phase I dose escalation study with an expansion cohort. Eligible adults had 1–4 brain metastases from solid malignancies. Sorafenib was begun 5–7 days prior to SRS and continued for 14 days thereafter. Dose escalation of sorafenib was conducted via a "3 + 3" dose escalation design. Dose limiting toxicities (DLT) were determined 1 month after SRS and defined as ≥grade 3 neurologic toxicities. Twenty-three patients were enrolled. There were no DLTs at dose level 1 (400 mg per day) or dose level 2 (400 mg twice per day). An expansion cohort of 17 patients was treated at dose level 2. There were six grade 3 toxicities: hypertension (n = 2), rash (n = 1), lymphopenia (n = 1), hypokalemia (n = 1), fatigue (n = 1) and hand-foot syndrome (n = 1). All of these were attributable to sorafenib and not to the combination with SRS. The median time to CNS progression was 10 months, 1 year CNS progression-free survival was 46%, the median overall survival was 11.6 months and the 1 year overall survival was 46%. The use of sorafenib concurrent with SRS for the treatment of 1–4 brain metastases is safe and well tolerated at 400 mg twice a day. Our recommended phase II dose of concurrent sorafenib with SRS would be 400 mg twice daily.

from Cancer via ola Kala on Inoreader http://ift.tt/2phQeie
via IFTTT

SPECT imaging and radionuclide therapy of glioma using 131 I labeled Buthus martensii Karsch chlorotoxin

Abstract

Gliomas, the most prevalent type of brain tumor in adults, are associated with high rates of morbidity and mortality. Recent studies on ¹³¹I labeled scorpion toxins suggest they can be developed as tumor-specific agents for glioma diagnosis and treatment. This study investigated the potential of ¹³¹I labeled Buthus martensii Karsch chlorotoxin (¹³¹I-BmK CT) as a new approach for targeted imaging and therapy of glioma. The results showed that ¹³¹I can be successfully linked to BmK CT with satisfactory radiochemical purity and stability and that ¹³¹I-BmK CT markedly inhibited glioma cell growth in a dose and time dependent manner, with significant accumulation in glioma cells in vitro. Persistent intratumoral radioiodine retention and specific accumulation of ¹³¹I-BmK CT were observed in C6 glioma tumor, which was clearly visualized by SPECT imaging. Both intratumoral and intravenous injections of ¹³¹I-BmK CT could result in significant tumor inhibition efficacy and prolonging the lifetime of tumor-bearing mice. Based on these promising results, it is concluded that ¹³¹I-BmK CT has the potential to be explored as a novel tool for SPECT imaging and radionuclide therapy of glioma.

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The 150 most important questions in cancer research and clinical oncology series: Questions 25–30

To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 6 more questi...

http://ift.tt/2qZBGAZ

Expenditure and financial burden for the diagnosis and treatment of colorectal cancer in China: a hospital-based, multicenter, cross-sectional survey

The increasing prevalence of colorectal cancer (CRC) in China and the paucity of information about relevant expenditure highlight the necessity of better understanding the financial burden and effect of CRC di...

http://ift.tt/2qp3gdT

Significance of spatial organization of chromosomes in the progression of acute myeloid leukemia

http://ift.tt/2qZs7C0

The 150 most important questions in cancer research and clinical oncology series: questions 15–24

To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 10 more quest...

http://ift.tt/2qoUFIl

Cancer metastasis: issues and challenges

Metastasis is the major cause of treatment failure in cancer patients and of cancer-related deaths. This editorial discusses how cancer metastasis may be better perceived and controlled. Based on big-data anal...

http://ift.tt/2qZAhuc

Expenditure and financial burden for the diagnosis and treatment of colorectal cancer in China: a hospital-based, multicenter, cross-sectional survey

The increasing prevalence of colorectal cancer (CRC) in China and the paucity of information about relevant expenditure highlight the necessity of better understanding the financial burden and effect of CRC di...

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via IFTTT

The 150 most important questions in cancer research and clinical oncology series: Questions 25–30

To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 6 more questi...

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via IFTTT

Significance of spatial organization of chromosomes in the progression of acute myeloid leukemia

from Cancer via ola Kala on Inoreader http://ift.tt/2qZs7C0
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The 150 most important questions in cancer research and clinical oncology series: questions 15–24

To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 10 more quest...

from Cancer via ola Kala on Inoreader http://ift.tt/2qoUFIl
via IFTTT

Cancer metastasis: issues and challenges

Metastasis is the major cause of treatment failure in cancer patients and of cancer-related deaths. This editorial discusses how cancer metastasis may be better perceived and controlled. Based on big-data anal...

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Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis

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Decreased levels of baseline and drug-induced tubulin polymerisation are hallmarks of resistance to taxanes in ovarian cancer cells and are associated with epithelial-to-mesenchymal transition

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Methylation of MYLK3 gene promoter region: a biomarker to stratify surgical care in ovarian cancer in a multicentre study

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Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma—experience of the BriTROC consortium

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Evaluating wait times from screening to breast cancer diagnosis among women undergoing organised assessment vs usual care

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Differential pattern of HIF-1α expression in HNSCC cancer stem cells after carbon ion or photon irradiation: one molecular explanation of the oxygen effect

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Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer

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Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study

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Serum inflammatory markers and colorectal cancer risk and survival

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A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation

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Towards better dose individualisation: metabolic phenotyping to predict cabazitaxel pharmacokinetics in men with prostate cancer

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Predicting breast cancer response to neoadjuvant chemotherapy using pretreatment diffuse optical spectroscopic texture analysis

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Targeting of CCBE1 by miR-330-3p in human breast cancer promotes metastasis

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Lithium enhances the antitumour effect of temozolomide against TP53 wild-type glioblastoma cells via NFAT1/FasL signalling

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Tyrosine kinase-targeting drugs-associated heart failure

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Tyrosine kinase-targeting drugs-associated heart failure

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Methylation of MYLK3 gene promoter region: a biomarker to stratify surgical care in ovarian cancer in a multicentre study

http://ift.tt/2pZZs1t

Differential pattern of HIF-1α expression in HNSCC cancer stem cells after carbon ion or photon irradiation: one molecular explanation of the oxygen effect

http://ift.tt/2pwLBNq

Evaluating wait times from screening to breast cancer diagnosis among women undergoing organised assessment vs usual care

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Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis

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Towards better dose individualisation: metabolic phenotyping to predict cabazitaxel pharmacokinetics in men with prostate cancer

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Targeting of CCBE1 by miR-330-3p in human breast cancer promotes metastasis

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Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer

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Decreased levels of baseline and drug-induced tubulin polymerisation are hallmarks of resistance to taxanes in ovarian cancer cells and are associated with epithelial-to-mesenchymal transition

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Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study

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Serum inflammatory markers and colorectal cancer risk and survival

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A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation

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Predicting breast cancer response to neoadjuvant chemotherapy using pretreatment diffuse optical spectroscopic texture analysis

http://ift.tt/2pwVudV

Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma—experience of the BriTROC consortium

http://ift.tt/2q0bVC9

Lithium enhances the antitumour effect of temozolomide against TP53 wild-type glioblastoma cells via NFAT1/FasL signalling

http://ift.tt/2q01jmY

Carfilzomib and lenalidomide response related to VEGF and VEGFR2 germline polymorphisms

Abstract

The combination of carfilzomib, lenalidomide, and dexamethasone (CRd) has induced deep responses in patients with newly diagnosed multiple myeloma. While vascular endothelial growth factor (VEGF) pathway polymorphisms have been associated with clinical outcomes for antiangiogenesis agents, we explored associations between such polymorphisms and CRd clinical response. The VEGF-1498C>T (rs833061) and VEGFR2 V297I (rs2305948) were associated with CRd response (OR ≤ 0.10, P ≤ 0.009), whereas VEGF-1498C>T and VEGFR2 Q472H (rs1870377) were associated with minimum residual disease negativity (P ≤ 0.023). As these SNPs were not associated with disease parameters (e.g., plasma VEGF, albumin, or beta-2-microglobin concentration), data suggest these SNPs may be markers of CRd response.

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Age and sex differences in microRNAs expression during the process of thymus aging

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The gender-biased thymus involution and the importance of microRNAs (miRNAs, miRs) expression in modulating the thymus development have been reported in many studies. However, how males and females differ in so many ways in thymus involution remains unclear. To address this question, we investigated the miRNA expression profiles in both untreated 3- and 12-month-old female and male mice thymuses. The results showed that 7 and 18 miRNAs were defined as the sex- and age-specific miRNAs, respectively. The expression of miR-181c-5p, miR-20b-5p, miR-98b-5p, miR-329-3p, miR-341-5p, and miR-2137 showed significant age-difference in mice thymus by quantitative polymerase chain reaction. High expression levels of miR-2137 were detected in mice thymic epithelial cells and gradually increased during the process of thymus aging. MiR-27b-3p and miR-378a-3p of the female-biased miRNAs were confirmed as the sex- and estrogen-responsive miRNAs in mice thymus <span style="font-style:italic;">in vivo</span>. Their potential target genes and the pathway were identified by the online software. Possible regulation roles of sex- and age-specific miRNA expression during the process of thymus aging were discussed. Our results suggested that these miRNAs may be potential biomarkers for the study of sex- and age-specific thymus aging and involution.</span>

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Toward the development of magnetic tweezers for high-throughput measurement of protein–protein interactions

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Age-dependent down-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 4 causes deterioration of canine sinoatrial node function

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The activity of pacemaker cells in the sinoatrial node (SAN) is an indicator of normal sinus rhythm. Clinical studies have revealed that the dysfunction of the SAN progressively increases with aging. In this study, we determined the changes in hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) expression and the relationship between aging and canine SAN dysfunction. The results of cardiac electrophysiological determination revealed that the intrinsic heart rate decreased from 168 ± 11 beats min⁻¹ in young canines to 120 ± 9 beats min⁻¹ in adults and to 88 ± 9 beats min⁻¹ in aged canines. The sinus node recovery time (SNRT) increased from 412 ± 32 ms in young canines to 620 ± 56 ms in adults and to 838 ± 120 ms in aged canines. Corrected SNRT (CSNRT) increased from 55 ± 12 ms in young canines to 117 ± 27 ms in adults and to 171 ± 37 ms in aged canines. These results indicated that SAN function deteriorated with aging in the canine heart. However, histological staining illustrated that fibrosis was not significantly increased with aging in canine SAN. Real-time polymerase chain reaction indicated that the expression of <span style="font-style:italic;">HCN4</span> mRNA was downregulated in the elderly canine SAN. Similarly, we also verified that HCN4 protein expression within the SAN declined with aging via immunofluorescence staining and western blot analysis. Taken together, our data show that electrical remodeling, related to the down-regulation of HCN4, is responsible for the gradually increased incidence of SAN dysfunction with aging. Our results provide further evidence for explaining the mechanisms of age-related deterioration in the SAN.</span>

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8-Bromo-7-methoxychrysin-blocked STAT3/Twist axis inhibits the stemness of cancer stem cell-like cell originated from SMMC-7721 cells

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Signal transducer and activator of transcription 3 (STAT3) is a member of the family of latent cytoplasmic transcriptional factors that could regulate cell proliferation, survival, and development. It has been reported that <span style="font-style:italic;">Twist</span> is a target gene of STAT3, and STAT3/Twist signaling plays an important role in regulating cancer progress. Here, to explore whether 8-bromo-7-methoxychrysin (BrMC) inhibits liver cancer stem-like cell (LCSLC) properties via disrupting STAT3/Twist signaling, we cultured SMMC-7721 cells <span style="font-style:italic;">in vitro</span>, and evaluated the effects of BrMC on the stemness of spheroids by determining the sphere-forming capability and migration. The sphere formation assay results showed a concentration-dependent decrease of sphere-forming capacity in LCSLCs (<span style="font-style:italic;">P</span> < 0.05) treated with different concentrations of BrMC. Wound-healing assays results demonstrated a concentration-dependent decline in cell migration of LCSLCs treated with different concentrations of BrMC. In addition, CD133, CD44, and ALDH1 levels were decreased in LCSLCs treated with BrMC. Treatment with different concentrations of BrMC also reduced the expressions of p-STAT3 and Twist1 proteins. The effect of BrMC was substantially enhanced by co-treatment with JSI-124, a specific inhibitor of STAT3. Ectopic expression of Twist1 attenuated the inhibitory effects of BrMC on sphere formation, migration, and expression of the markers in LCSLCs. However, it had no affect on p-STAT3 expression in LCSLCs. These results demonstrated that BrMC inhibits the stemness of LCSLCs originated from SMMC-7721 cell line by inhibiting STAT3/Twist signal axis.</span>

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Protective role and related mechanism of Gnaq in neural cells damaged by oxidative stress

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Gnaq is a member of G protein family and is rich in brain tissue. It has attracted the attention of many researchers in melanoma due to its high ratio of mutation. We have previously reported that the expression level of Gnaq in the mouse forebrain cortex was significantly decreased with age. Oxidative stress (OS) is the main cause leading to brain aging and related diseases. The roles and mechanisms of Gnaq in antioxidation in the brain have not been fully explored. In the present study, gene recombinant technique and lentivirus transfection technique were used to generate a Gnaq-overexpression cell model (Gnaq-SY5Y) coupled with H₂O₂ to build an OS model. The viability of cells, concentration of reactive oxygen species (ROS), apoptosis-related proteins (Bcl-2 and Bax), and signal pathways (NF-κB and Erk1/2) were compared between model cells and control cells. Results showed that the antioxidative ability of Gnaq-SY5Y cells was significantly improved. Concomitantly, the ROS level in Gnaq-SY5Y cells was significantly decreased whether the cells were subject to or not to H₂O₂ treatment. Anti-apoptotic protein Bcl-2 was up-regulated and apoptosis-promoting protein Bax was down-regulated in Gnaq-SY5Y cells after treatment with H₂O₂. NF-κB and phosphorylated Erk1/2 (p-Erk1/2) was significantly down-regulated in Gnaq-SY5Y cells. H₂O₂ treatment decreased Gnaq expression but increased NF-κB and p-Erk1/2 expressions in Gnaq-SY5Y cells. It is therefore concluded that Gnaq plays a pivotal role in antioxidation in neural cells. A possible mechanism for this would be that the overexpressed Gnaq inhibits the cellular damaging effect mediated by NF-κB and Erk1/2 signal pathways.</span>

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MiR-218 suppresses the metastasis and EMT of HCC cells via targeting SERBP1

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. Although many efforts for treating HCC have been made, the survival rate remains unsatisfied. Accumulating evidence indicates that microRNA-218 (miR-218) functions as a tumor suppressor and involves in many biological processes such as tumor initiation, development, and metastasis in certain types of human cancers. However, the potential function and underlying molecular mechanism of miR-218 in HCC still remains to be elucidated. Since HCC is a genetic disease, exploring the mechanisms of the pathogeny and integration are essential for the discovery of novel treatment targets for HCC. Therefore, the aim of the present study was to investigate the abnormal expression level of miR-218 in clinical HCC tissues and HCC cells, and to evaluate its function and underlying mechanisms in HCC. Our results revealed that miR-218 expression was significantly downregulated in HCC tissues and cell lines. Gain-of-function and loss-of-function assays indicated that forced expression of miR-218 in HCC cells inhibited cell migration/invasion and reversed epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET), while deletion of miR-218 promoted cell migration/invasion and contributed to the EMT phenotype formation. Bioinformatics analysis and luciferase reporter assay confirmed that serpine mRNA binding protein 1 (SERBP1) was a target gene of miR-218 and rescue assay further confirmed that SERBP1 involved in the function of miR-218 in HCC. All these results suggested that miR-218/SERBP1 signal pathway could inhibit the malignant phenotype formation and that targeting this pathway may be a potential novel way for HCC therapeutics.</span>

http://ift.tt/2ptinOJ

Molecular cloning and characterization of antimicrobial peptides from skin of Hylarana guentheri

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The cDNAs encoding antimicrobial peptides (AMPs) in the skin of <span style="font-style:italic;">Hylarana guentheri</span> were identified, namely temporin (five peptides, termed temporin-GHa–GHd and temporin-GUa), brevinin-1 (one peptide, brevinin-1GUb), and brevinin-2 (eight peptides, brevinin-2GHd–2GHj, and brevinin-2GHb). Eleven of the 14 peptides have novel primary structures. Synthesized temporin GHa-GHd have broad-spectrum antimicrobial activities against Gram-positive bacteria (<span style="font-style:italic;">Staphylococcus aureus</span> and <span style="font-style:italic;">Bacillus subtilis</span>), Gram-negative bacteria (<span style="font-style:italic;">Escherichia coli</span>, <span style="font-style:italic;">Vibrio alginolyticus</span>, and <span style="font-style:italic;">Pseudomonas aeruginosa</span>), as well as fungus (<span style="font-style:italic;">Candida albicans</span>). Among these tested strains, <span style="font-style:italic;">S. aureus</span> was the most sensitive to temporin-GHa–GHd with minimum inhibitory concentration (MIC) values between 6.8 and 12.9 μM. They also exhibited antimicrobial activities against Methicillin-resistant <span style="font-style:italic;">S. aureus</span> with the MIC ranging from 12.7 to 51.7 μM. Interestingly, secondary structure prediction shows that there is no α-helix in temporin-GHb, which illustrates that α-helix is not required for the antimicrobial activity of temporin-GHb. NaCl (at final concentrations of 0.15–2 M) decreased the antimicrobial activity of temporin-GHa–GHd slightly, while human serum and <span style="font-style:italic;">S. aureus</span> V8 proteinase had no effect on the antimicrobial activity. Scanning electron microscopy images of <span style="font-style:italic;">E. coli</span> and <span style="font-style:italic;">S. aureus</span> showed that the surface of microbial cells was considerably rough and shrived after 1 h of treatment with temporin-GHa–GHd at 37°C. The stabilities of temporin-GHa–GHd in human serum or in <span style="font-style:italic;">S. aureus</span> V8 proteinase make them to be promising candidates of novel antimicrobial agents or models for the development of novel AMPs.</span>

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Progressive silencing of the zinc transporter Zip8 (Slc39a8) in chronic cadmium-exposed lung epithelial cells

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Cadmium (Cd), a non-essential metal, stealthily enters the cells by utilizing the essential metal importing pathways. The zinc transporters Zip8, Zip14, and divalent metal transporter 1 (Dmt1) are now emerging as several important metal transporters involved in cellular Cd incorporation and their expressions have been shown to be down-regulated in several Cd-resistant (Cd^R) cell lines, however, the involvement of these transporters during the development of Cd-resistance in lung cells is unclear. In this study, we therefore check the expression of these metal transporters in our previously established rat lung epithelial cells (LECs) and show that the level of Zip8 is progressively silenced when LECs are adapted to increasing concentrations of CdCl₂ (from 1 to 20 μM). Subsequent measurement of the cellular Cd content indicated that Cd^R LECs exhibit a marked decrease of Cd accumulation, possibly due to the loss of Zip8 expression. We investigate the possibility that epigenetic silencing of the <span style="font-style:italic;">Zip8</span> gene by DNA hypermethylation is involved in the down-regulation of Zip8 expression. Cd^R LECs show a higher mRNA level of DNA methyltransferase 3b (Dnmt3b) than parental cells. Treatment of Cd^R LECs with 5-aza-2′-deoxycytidine, an inhibitor of DNA methyltransferases, reverted the expression of Zip8 and sensitivity to Cd in these cells, indicating the critical role of Zip8 for Cd import. Taken together, our results demonstrate that the progressive silencing of Zip8 expression is involved in the acquisition of resistance against Cd in lung cells, representing an adaptive survival mechanism that resists Cd-induced cytotoxicity.</span>

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Recombinant CC16 protein inhibits the production of pro-inflammatory cytokines via NF-κB and p38 MAPK pathways in LPS-activated RAW264.7 macrophages

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Accumulating evidence indicates that Clara cell protein-16 (CC16) has anti-inflammatory functions, although the involved molecular pathways have not been completely elucidated. Here, we evaluated the effect of recombinant rat CC16 (rCC16) on the expression of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-8 in lipopolysaccharide (LPS)-stimulated mouse macrophages (RAW264.7 cells) and explored the underlying molecular mechanisms. It was found that rCC16 inhibited LPS-induced TNF-α, IL-6, and IL-8 expression at both the messenger ribonucleicacid (mRNA) level and protein level in a concentration-dependent manner, as demonstrated by real-time reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Such suppressive effects were accompanied by the inhibition of transcriptional activity and the deoxyribonucleic acid binding activity of nuclear factor (NF)-κB but not activator protein (AP)-1. Western blot analysis further revealed that rCC16 inhibited the increase of nuclear NF-κB and the reduction of cytosolic NF-κB, the phosphorylation and reduction of NF-κB inhibitory protein IκBα, and the p38 mitogen-activated protein kinase (MAPK)-dependent NF-κB activation by phosphorylation at Ser276 of its p65 subunit. Furthermore, rCC16 was found to have no effect on the phosphorylation of c-Jun N-terminal kinase, c-Jun, or the nuclear translocation of c-Jun. In addition, reduction of TNF-α, IL-6, and IL-8 were reversed when the level of endogenous uteroglobin-binding protein was reduced by RNA interference in rCC16- and LPS-treated RAW264.7 cells. Our data suggest that rCC16 suppresses LPS-mediated inflammatory mediator TNF-α, IL-6, and IL-8 production by inactivating NF-κB and p38 MAPK but not AP-1 in RAW264.7 cells.</span>

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Dihydrocelastrol inhibits multiple myeloma cell proliferation and promotes apoptosis through ERK1/2 and IL-6/STAT3 pathways in vitro and in vivo

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Multiple myeloma (MM) is the second most frequent malignant hematological disease. Dihydrocelastrol (DHCE) is synthesized by hydrogenated celastrol, a treterpene isolated from Chinese medicinal plant <span style="font-style:italic;">Tripterygium regelii</span>. In this study, we first reported the anti-tumor activity of DHCE on MM cells. We found that DHCE could inhibit cell proliferation and promote apoptosis through caspase-dependent way <span style="font-style:italic;">in vitro</span>. In addition, DHCE could inactivate the expression of interleukin (IL)-6 and downregulate the phosphorylation of extracellular regulated protein kinases (ERK1/2) and the signal transducer and activator of transcription 3 (STAT3) in MM. It also retained its activity against MM cell lines in the presence of IL-6. Furthermore, treatment of MM cells with DHCE resulted in an accumulation of cells in G₀/G₁ phase of the cell cycle. Notably, DHCE reduced the expression of cyclin D1 and cyclin-dependent kinases 4 and 6 in MM cell lines. Additionally, its efficacy toward the MM cell lines could be enhanced in combination with the histone deacetylase inhibitor panobinostat (LBH589), which implied the possibility of the combination treatment of DHCE and LBH589 as a potential therapeutic strategy in MM. In addition, treatment of NCI-H929 tumor-bearing nude mice with DHCE (10 mg/kg/d, i.p., 1–14 days) resulted in 73% inhibition of the tumor growth <span style="font-style:italic;">in vivo</span>. Taken together, the results of our present study indicated that DHCE could inhibit cellular proliferation and induce cell apoptosis in myeloma cells mediated through different mechanisms, possibly through inhibiting the IL-6/STAT3 and ERK1/2 pathways. And it may provide a new therapeutic option for MM patients.</span>

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miR-30e is negatively regulated by myostatin in skeletal muscle and is functionally related to fiber-type composition

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Myostatin (MSTN) negatively regulates skeletal myogenesis in which microRNAs (miRNAs) also play critical roles. Using miRNA microarrays of skeletal muscle from MSTN-knockout (MSTN^−/−) mice, we recently showed that miR-431 is regulated by MSTN signaling. To identify additional miRNAs regulated by MSTN, we re-analyzed these miRNA arrays and validated their expression by quantitative RT-PCR. Herein, we demonstrated that miR-30e was significantly upregulated in skeletal muscle of MSTN^−/− mice compared with that of the wild-type littermates. Importantly, the predicted targets of miR-30e are functionally involved in myocyte differentiation and fiber-type formation. Using luciferase reporter gene assays, we further showed that peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (<span style="font-style:italic;">Pgc1α</span>), is a direct target of miR-30e. Overexpression of miR-30e in C2C12 cells significantly decreased <span style="font-style:italic;">Pgc1α</span> and increased type II form of myosin heavy chain gene expression, suggesting that miR-30e functionally associates with glycolytic myofiber formation. Thus, our data indicate that the altered fiber-type composition in MSTN^−/− mice are attributable in part to deregulated expression of miR-30e.</span>

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Improved clearing of lipid droplet-rich tissues for three-dimensional structural elucidation

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Carfilzomib and lenalidomide response related to VEGF and VEGFR2 germline polymorphisms

Abstract

The combination of carfilzomib, lenalidomide, and dexamethasone (CRd) has induced deep responses in patients with newly diagnosed multiple myeloma. While vascular endothelial growth factor (VEGF) pathway polymorphisms have been associated with clinical outcomes for antiangiogenesis agents, we explored associations between such polymorphisms and CRd clinical response. The VEGF-1498C>T (rs833061) and VEGFR2 V297I (rs2305948) were associated with CRd response (OR ≤ 0.10, P ≤ 0.009), whereas VEGF-1498C>T and VEGFR2 Q472H (rs1870377) were associated with minimum residual disease negativity (P ≤ 0.023). As these SNPs were not associated with disease parameters (e.g., plasma VEGF, albumin, or beta-2-microglobin concentration), data suggest these SNPs may be markers of CRd response.

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Clinical utility of a self-administered questionnaire for assessment of hereditary gynecologic cancer

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>A patient's medical history and familial cancer history are important information for assessing the risk of hereditary cancer. We have generated a self-administered questionnaire for patients with gynecologic cancer. This pilot study analyzed the usefulness of this questionnaire and the rates of patients that meet the Society of Gynecologic Oncology criteria in ovarian cancer and endometrial cancer patients.<div class="boxTitle">Method</div>Ovarian or endometrial cancer patients were recruited for this study. After informed consent was obtained, participants completed the questionnaire. Genetic risks were assessed from the data of each patient's questionnaire by Society of Gynecologic Oncology guideline. Clinical and pathological findings were compared between the genetic risk groups.<div class="boxTitle">Results</div>A total of 105 patients were identified with ovarian cancer and 56 patients with endometrial cancer eligible for this study. According to the Society of Gynecologic Oncology guideline, of the 105 ovarian cancer patients, 25 patients (23%) had a 20–25% risk and three patients (2.9%) had a 5–10% risk of hereditary breast and ovarian cancer syndrome. A further 22 patients (21%) had a 5–10% risk of Lynch syndrome. Two patients (1.9%) met the Amsterdam criteria II. Of 56 endometrial cancer patients, 24 patients (42.9%) had a 5–10% risk of Lynch syndrome. The endometrial cancer patients with genetic risk of Lynch syndrome were younger (mean age: 47.79) at diagnosis compared to patients without a genetic risk of Lynch syndrome (mean age: 57.91).<div class="boxTitle">Conclusions</div>In this study, we were able to show that the newly designed questionnaire is a useful tool for evaluating cancer family history along with Society of Gynecologic Oncology criteria or Amsterdam criteria II. When considering the risk of Lynch syndrome for a patient with ovarian cancer, it is important to collect a second and third relative's family history.</span>

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IN THIS ISSUE

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Incidence rate for larynx cancer in Japanese in Japan and in the United States from the Cancer Incidence in Five Continents

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Clinical utility of a self-administered questionnaire for assessment of hereditary gynecologic cancer

http://ift.tt/2q1hjp6

Spontaneous regression of melanoma—letting us reaffirm the significance of immunotherapy

http://ift.tt/2q48J7b

Significance of primary lesion resection in Stage IV breast cancer

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Systemic treatment with drugs is administered to prolong survival and palliate symptoms in Stage IV breast cancer patients who have distant metastases at diagnosis. Surgical procedures for the primary tumor are not actively recommended in guidelines due to lack of evidence indicating prognostic benefit. Recently, several retrospective studies have shown primary tumor resection to prolong overall survival in patients with Stage IV breast cancer. Prospective randomized trials began enrolling patients to examine this possibility and two have already reported results. However, the results of these two trials were discordant. The first trial, conducted in India, reported negative effects of primary tumor resection after primary systemic therapy. A Turkish trial then obtained a positive effect of surgery as primary treatment. Several questions regarding the effects, timing, methods and eligibility for primary surgery have yet to be answered. Robust evidence, which is anticipated from other ongoing trials examining surgery for metastatic breast cancer, is eagerly awaited.</span>

http://ift.tt/2q1nLMC

Discomfort during bronchoscopy performed after endobronchial intubation with fentanyl and midazolam: a prospective study

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objective</div>Although endobronchial intubation during a bronchoscopic examination is useful for invasive procedures, it is not routine practice in Japan. The present study evaluated discomfort due to endobronchial intubation using fentanyl and midazolam sedation during bronchoscopy.<div class="boxTitle">Methods</div>Thirty-nine patients were enrolled prospectively from November 2014 to September 2015 at Okayama University Hospital. Fentanyl (20 µg) was administered to the patients just before endobronchial intubation, and fentanyl (10 µg) and midazolam (1 mg) were added as needed during the procedure. A questionnaire survey was administered 2 h after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: excellent (1 point), good (2 points), normal (3 points), uncomfortable (4 points) and very uncomfortable (5 points). An additional question ('Do you remember the bronchoscopic examination?') was also asked. Predefined parameters (blood pressure, heart rate, oxygen saturation and complications) were recorded.<div class="boxTitle">Results</div>The enrolled patients included 22 males and 17 females; their median age was 70 (range: 28–88) years. The patients received a mean dose of 47.9 µg of fentanyl (range: 30–90 µg) and 2.79 mg of midazolam (range: 1–7 mg). In total, 28 patients (71.7%) agreed to undergo a second bronchoscopic examination; the mean levels of discomfort and for the re-examination were 2.07 points each. About 41% of the patients remembered the bronchoscopic examination. No severe complications were reported.<div class="boxTitle">Conclusion</div>Endobronchial intubation using fentanyl and midazolam sedation during an invasive bronchoscopic procedure might be recommended.<div class="boxTitle">Clinical Trial Registration</div>UMIN000015578 in the UMIN Clinical Trials Registry</span>

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Clinical outcome of definitive radiation therapy for superficial esophageal cancer

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objective</div>To analyze the clinical outcome of concurrent chemoradiotherapy in superficial esophageal cancer patients.<div class="boxTitle">Methods</div>We retrospectively analyzed data for 123 patients with superficial esophageal cancer who received external beam radiotherapy without intracavitary brachytherapy plus systemic chemotherapy during 1998–2015. Elective nodal irradiation was not performed. The dosage to planning treatment volume was 60 Gy in 30 fractions. The main outcome measure was overall survival.<div class="boxTitle">Results</div>Patient characteristics were as follows: median age, 66 (41–83) years; male/female ratio, 106/17; squamous cell carcinoma/other, 122/1; cT1a/cT1b, 27/96; cervical esophagus/upper thoracic esophagus/middle thoracic esophagus/lower thoracic esophagus, 7/9/66/41 and concurrent chemoradiotherapy/radiotherapy alone, 100/23. Cisplatin and 5-fluorouracil were the most commonly used agents (85%). At the last follow-up (median 60.5 months), 91 (74%) patients were alive. Complete response was achieved in 116 (94.4%) patients. The 5-year overall survival, progression-free survival and local control rates were 77.0, 46.9 and 62.7%, respectively, similar to that in the elderly patients (<span style="font-style:italic;">P</span> = 0.878, 0.754 and 0.648, respectively). There were 55 failures: 42 local, 10 regional and 3 distant failures. Nine local and seven regional failures developed out-of-field. Thirty-eight local failures (90%) were successfully salvaged, of which 30 (71%) were salvaged via endoscopic removal; only 2 regional failures (20%) were salvaged. Fifteen G3 acute toxicities occurred. One pneumonitis (G3), one pneumothorax (G3) and two pericardial effusion (G2) were the late toxicities observed. There were no G4 toxicities or treatment-related deaths.<div class="boxTitle">Conclusions</div>Concurrent chemoradiotherapy without intracavitary brachytherapy was effective and safe for superficial esophageal cancer, even in elderly patients.</span>

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